This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Many important pathogens of humans and animals belong to the positive-sense, single-stranded RNA viruses. Enzymes such as RNA polymerase and the chymotrypsin-like proteases are absolutely required for viral replication. Therefore, these enzymes and their precursors are ideal targets for the design of antiviral drugs. We and others have determined crystal structures of a number of viral enzymes from this group, including some with bound inhibitors. This work is valuable for the understanding of viral evolution, enzymatic mechanisms and the development of anti viral drugs. We are pursuing a project to develop different and more effective inhibitors of several viral enzymes.